Swine Flu Connection Provides Clues About Narcolepsy

The swine flu pandemic of late 2009 had a peculiar aftereffect in parts of Europe: a spike in children being diagnosed with narcolepsy, an incurable sleep disorder with symptoms including bouts of overwhelming daytime sleepiness. Researchers eventually linked a vaccine widely used to stave off the H1N1 flu virus to a small but increased risk of narcolepsy in children and teens. The vaccine, Pandemrix, used only in Europe, apparently triggered the disorder in roughly one out of 16,000 recipients in Finland. Sweden, Ireland, and England also found an increased risk, though not as dramatic as Finland’s.

Now, scientists have a clue to why—one that points to a new understanding of narcolepsy itself, they report this week in Science Translational Medicine. They found that patients with the disease have immune cells that are spurred to attack by hypocretin, a hormone that regulates wakefulness. Scientists knew that the neurons that produce hypocretin are missing in narcoleptic brains, but why they disappear is a mystery. The work reveals “the fingerprints of an immune attack,” says neuroimmunologist Lawrence Steinman of Stanford University in Palo Alto, California, who was not involved in the research. It suggests that an autoimmune reaction, perhaps touched off by Pandemrix, could underlie the vaccine-linked cases. The researchers also speculate that flu itself might trigger other cases.

When the association between Pandemrix and narcolepsy showed up, the vaccine’s maker, GlaxoSmithKline, funded research to investigate what, if anything, in the vaccine could trigger the disease. Narcolepsy researcher Emmanuel Mignot of Stanford University, who received one of the grants, already suspected that rogue immune cells might contribute to narcolepsy. In 2009, Mignot and colleagues had found that almost all narcolepsy patients have a particular human leukocyte antigen (HLA) type. HLA molecules present antigens—pieces of foreign proteins—to T cells, which then coordinate the immune system’s attack. The process helps the immune system distinguish between self and foreign cells, and certain HLA types are associated with autoimmune diseases such as type 1 diabetes and multiple sclerosis. But there is no obvious sign of immune attack in narcoleptic brains.

In the new work, Mignot, Stanford immunologist Elizabeth Mellins, and colleagues developed an immune system cell line that carries the HLA type associated with narcolepsy. They combined the cell line with short pieces of the hypocretin protein, then added T cells from patients and controls to the mix.

The team had access to four sets of identical twins in which one twin had narcolepsy but the other didn’t. In each case, T cells from the affected twin reacted strongly to the hypocretin “epitopes” displayed by the HLA-bearing cells, but T cells from the healthy twin did not. The researchers found the same pattern when they compared T cells from 10 Irish children who had developed narcolepsy after receiving the Pandemrix vaccine with T cells from the patients’ healthy siblings, all of whom had the same HLA type and were also vaccinated. The patients’ T cells reacted to the hypocretin epitopes, while their siblings’ cells did not.

They then wondered whether the H1N1 virus itself might provoke the same immune reaction. A computer search turned up certain stretches of a key part of the H1N1 virus, the hemagglutinin protein, that “looked strikingly the same” as the hypocretin epitopes, Mignot says. Sure enough, in lab tests the viral protein fragment activated hypocretin-reactive immune cells—strong evidence that narcolepsy could be due to a process known as molecular mimicry, in which protein fragments from an invading virus or other pathogen prime the immune system to react to native proteins with a similar molecular structure.

The results are “exactly what we’ve been waiting for,” says vaccine expert Hanna Nohynek of the National Institute for Health and Welfare in Helsinki, who was part of the team that first identified the increased risk of narcolepsy in children who received Pandemrix.

But molecular mimicry alone can’t explain the whole mystery. It’s not clear how an immune response to hypocretin could lead to the destruction of the neurons that produce it, as reactive cells in the blood would not necessarily reach these brain cells.

And it is still unclear whether H1N1 flu alone might trigger narcolepsy. Mignot and his colleagues have reported an increase in the disorder among unvaccinated Chinese children who had the virus. But researchers in South Korea and Europe have found no increased risk of the disorder in people who had swine flu.

“There’s plenty of work to do,” says vaccine expert Steven Black of Cincinnati Children's Hospital Medical Center in Ohio, who is investigating possible links between H1N1 vaccines and narcolepsy. But the work “is the first mechanistic explanation of the disease,” which should help researchers home in on the factor in Pandemrix that might have caused problems. Identifying that, he says, “is a first step” to being able to make even safer vaccines.